Disruption of signaling through the CD40-CD40L system 1) reduces the deposition of Abeta (amyloid-beta peptide) in the brains of APP (amyloid precursor protein) overproducing transgenic mice, 2) slows the maturation of activated microglia from a phagocytic to an antigen presenting phenotype with attendant increased production of cytokines linked to inflammation (IL-beta1 and TNF-alpha) and 3) promotes anti-inflammatory responses, including increased levels of CNS (central nervous system) TGF-beta1 and IL-10, which further benefits the microglial phagocytosis. Vaccination with the Abeta peptide reduces Abeta deposition in APP overexpressing transgenic mice and ameliorates the memory disruption associated with excess brain Abeta. Clinical trials of Abeta immunotherapy were halted because of CNS inflammation in a subset of cases. In spite of cessation of further vaccine inoculations, the first reports from this trial suggest some success in slowing the rate of dementia progression in patients generating antibodies against brain Abeta. Two major hypotheses regarding the actions of Abeta immunotherapy are the facilitation of microglial phagocytosis via Fc receptors and promotion of Abeta removal from the brain by increasing the brain/blood concentration gradient via anti-Abeta antibody peripheral sink. This application proposes to test the hypothesis that the actions of anti-Abeta therapy and anti-CD40L signaling therapy will be mutually beneficial as a co-administrated AD (Alzheimer's disease) immunotherapy strategy. In addition, the anti-CD40L antibody is predicted to abrogate the potential adverse effects of the anti-Abeta immunotherapy by increasing anti-inflammatory cytokines in the CNS (i.e. TGF-beta1 and IL-10), as well as by slowing the maturation of the microglia into the proinflammatory antigen presenting phenotype. This latter property may be beneficial for patients even with improved vaccine preparations that lack inflammation response properties. In this proposal, we will focus on 1) CD40 signaling modulation of microglial phagocytic and antigen presentation phenotypes; 2) CD40-CD40L blockage synergizes with Abeta vaccination in mitigating AD-like pathology and cognitive impairment; 3) ICV (intracerebroventrocular) administration of anti-CD40L antibody in attenuation of AD-like pathology.